Download SIADH, DI and Cerebral Salt Wasting

SIADH, DI and Cerebral Salt
Wasting
Karim Rafaat, MD
ADH
ADH is produced in cells
osmoreceptors
in the supraoptic and
paraventricular nuclei
supraoptic
It is transported to and neurons
released from the
posterior pituitary
Drain into cavernous sinus
ant.
and IVC
paraventricular
neurons
baroreceptor
input
pons
pituitary
post.
ADH
Secretion of ADH
• Most important variable is
osmotic pressure of
plasma and ECF.
– Largely a function of the
concentration of Na
• Osmoregulation mediated
by osmoreceptors in the
anteromedial
hypothalamus near the
suraoptic nucleus
– Blood supply is via
fenestrated capillaries, and
so they are outside BBB
osmoreceptors
paraventricular
neurons
baroreceptor
input
supraoptic
neurons
ant.
pituitary
post.
pons
ADH
ADH secretion
• Osmoreceptors are sensitive to small
changes in plasma osmolality
• A decrease in osmolality of 1-2% will
maximally and rapidly suppress ADH levels
to allow diuresis
• The osmostat set point in adults is a
plasma osmolality of 275-295 mOsm/kg
ADH Secretion
• ADH also released in response to nonosmotic variables
– Decrease in blood volume or arterial pressure
of more than 10-20%
• These are mediated by neural pathways that
originate in pressure sensitive receptors in the wall
of the LA and projects via the vagal and
glossopharyngeal nerves to the brain stem
– Have little function in normal physiologic states
ADH Function

In the collecting duct
blood-borne ADH binds to a
V2 receptor on the basolateral surface of the
principal tubule cell.
Tubule
H2 O
H2 O
Prot
cAMP
kinase
AR
C ec

This stimulates adenylyl
cyclase to generate cAMP
and activate protein kinases.

This increases the
insertion of water channels,
aquaporins, into the apical
surface of the cell and so
increase water permeability
ADH
ATP
H2 O
H2 O
• When the collecting ducts are permeable,
water filters down the osmotic gradient in
the medulla
– Plasma [ADH] between 0.5 and 5 pg.ml-1
accounts for the range of urine osmolalities
i.e. 100 - 1250 mosmol.kg H2O-1.
• Without ADH, the collecting duct cells are
impermeable to water
• ADH also acts on V1 receptors, acting as a
vasopressor
– This causes an increase in effective plasma volume,
which can then downregulate ADH secretion through
its action on the LA baroreceptors
• V3 receptors mediate ACTH secretion from the
pituitary
• V2 receptors also act to increase Factor VIII
production
Distribution and Clearance of ADH
• ADH circulates in an unbound state and
equilibrates within minutes between
plasma and ECF
• Average half life is 20 minutes
• 15-20% is filtered by glomerulus and then
either destroyed or excreted.
• The rest is degraded in the liver
ADH and Thirst: salt and water
balance
• ADH function is limited, because it cannot
prevent water loss in excess of that
needed to excrete a certain solute load.
– Another mechanism is needed to ensure that
these, and other losses are replaced…
• THIRST
ADH and Thirst: salt and water
balance
Plasma osmolality ≈ 290 mosmoles. kg H2O-1.
water lack
increased osmolality
osmoreceptors
excessive water intake
decreased osmolality
osmoreceptors
supraoptic
PVN nuclei
lateral preoptic area
lateral pre- supraoptic
optic area PVN nuclei
ADH release
increased
thirst
enhanced
thirst
ADH release
depressed
reduced
collecting duct
more permeable
drinking
water retention
by kidneys
collecting duct
less permeable
water loss
by kidneys
Disorders of ADH secretion or
action
Diabetes Insipidus
Diabetes Insipidus
• Characterized by
– A large volume of urine (diabetes)
– That is hypotonic, dilute and tasteless
(insipid)
• Versus the sweet urine of diabetes mellitus
(honey)
Etiology
• Four fundamentally distinct defects
– Central DI, a primary deficiency of ADH
– Nephrogenic DI, caused by an inappropriate
renal response to ADH
– Transient DI of pregnancy, caused by
vasopressinase produced by placenta
– Primary Polydipsia, in which pathology is
secondary to ingestion, rather than
elimination of, fluid
Central DI
• Most common
• Usually secondary to irreversible
destruction of >80% ADH producing
neurons
• Genetic forms caused by accumulation of
poorly folded precursor proteins
Genetic
Congenital
Acquired
Chromosome 20 –dominant
Septo-optic dysplasia
Head trauma
X linked (Xq28)
Cleft lip and palate
Neoplasms
craniopharyngioma, adenoma,
lymphoma
Wolfram syndrome
Holoprosencephaly
Granulomas
Agenisis/hypogenisis of pit
Infections
meningitis, encephalitis, toxo
Autoimmune
lupus, scleroderma, wegener’s
Toxins (snakes)
Vascular
sheehan’s
HIE
Central DI
• In the OR/ICU - trauma
– 4 year retrospective review of all ICU trauma
admissions
– DI secondary to trauma occurs as a complication
2.9% of the time
– Overall mortality 69%
– All patients that died developed DI within the first
three days
• Increased Mortality to 86%
Boughey,JC DI in the head injured patient, Am Surj; Jun 2004
Central DI
• Head Trauma
– DI is often triphasic in nature
• 1st phase, DI, occurs within 24 hours of injury and is due to
•
axon shock and inability to propogate action potentials to the
terminals in the post pit.
2nd phase, antidiuretic phase, due to unregulated release of
ADH from posterior pituitary stores as the axons die
– This phase can occur post head injury, without 1st and 3rd
phases
• 3rd phase, return of DI, occurs after all the hormone has
been released
Central DI
• In the ICU/OR - Neurosurg
– Occurs commonly in children with hypothalamic,
pituitary or optic tumors
• Craniopharyngioma is the most common non-glial tumor in
the pediatric age group
– DI develops in approx 80% of patients post-op
• Occurs in 75% of patients following pituitary tumor resection
– Most resolve post-op, 6% is permanent
Wise,L Perioperative management of DI in children, Journal of Neurosurgical
Anesthesiology; Jan 2004
Nephrogenic DI
• Caused by a poor response of the kidney
to ADH
• Most common form is congenital
• Other forms are acquired
Genetic
Acquired
X linked (V2 gene)
Drugs
lithium, Ampho B, rifampin, cisplatin,
foscarnet
Recessive (aquaporin gene)
Metabolic
hypercalcemia, hypercalcuria,
hypokalemia
Vascular
sickle cell disease, ischemia
Granuloma
Neoplasm
Pathophysiology
• Lack of ADH, or ADH response, leads to a
deficiency in urine concentration
– 1-2% decrease in TBW, and a rise in plasma
osmolality and Na
• The latter cause a thirst response, which, if intact,
stabilizes osmo’s and Na
• Polyuria further impairs concentrating
ability through washout of medullary
concentration gradient
Diagnosis
• Lots of stuff about fluid restriction, ADH
levels, DDAVP trials, MRI’s….not useful for
us
– Useful for distinguishing between nephrogenic
and central forms
• Endocrine consult
• There is a much easier way to get what
we need, and is based on simple
pathophysiology
Diagnosis
• CLINICAL SUSPICION
– Bad brain injury, neurosurg post-op
• High or increasing urine output
– Urine Osmo usually < 300mOsm/kg
• Increasing serum Na
– Implies free water loss in excess of sodium
loss, which implicates ADH as the culprit
Treatment
• Vasopressin
– 5-10 mUnits/kg/hr
– Titrate to a level that normalizes urine output and stabilizes
serum Na
• DDAVP
– For chronic correction
– More resistant than vasopressin to degradation
– 5-20 micrograms/day by nasal spray
• Oral and SQ forms available
• If nephrogenic
– Sodium restriction and mild diuresis to encourage Na elimination
– Gene therapy in the works…..
SIADH
SIADH
• Characterized by
– Hypotonic hyponatremia
– impaired urinary dilution in the face of hypoosmolality
• Urine osmolality >100mOsm/kg
– In the absence of:
• Hypovolemia
• Hypotension
• Adrenal insufficiency
• Protracted emesis
SIADH
• One of the most common causes of
hyponatremia in children and adults, in
the hospital setting
Etiology
Ectopic
Pituitary hypersecretion
Neoplasm
carcinoma of the
bronchus, ovary, bladder; mesothelioma; sarcoma
Neoplasm
carcinoma of bronchus
Drugs
DDAVP, vasopressin, oxytocin
Drugs
carbamazepine, nicotine, TCA, MAOI, SSRI,
vincristine
Head Trauma
Infections
pneumonia, abcess of lung or brain, TB,
encephalitis, meningitis
Pulmonary
asthma, PTX, POSITIVE PRESSURE
VENTILATION
Neurologic
GBS, MS, hydrocephalus, cerebrovascular
occlusion or hemorrhage
• Most common causes
–
–
–
–
–
–
PNA
Bronchiolitis
Asthma
PPV
CNS infections
Head trauma
Pathophysiology
• ADH cannot significantly lower plasma Na, unless water
•
•
•
•
input > output
When this occurs, the excess ADH makes a making a
dilute urine difficult
Water accumulates in ECF and ICF compartments
Conc of Na and other solutes decreases
Renin and aldosterone activity decreases
– Increases natriuresis as a response to expansion of ECF volume
• Natriuresis aggravates dilutional hyponatremia
The case against hypotonic
maintenance fluids
• Many common etiologic agents cause SIADH
• Current recommendations for maintenance fluids
are for hypotonic 1/2NS
• SIADH + hypotonic fluids can lead to an acute
and symptomatic hyponatremia
• >50 reported cases of neurologic morbidity,
including 26 deaths, resulting from hospital
acquired hyponatremia in children receiving
hypotonic fluids
The case against hypotonic
maintenance fluids
• Children at greater risk for symptomatic
hyponatremia than adults
– Encephalopathy occurs at higher values in
kids
• Higher brain to skull ratio leaves less room for
expansion
The case against hypotonic
maintenance fluids
• Moritz et al, Prevention of hospital acquired
hyponatremia: a case for using isotonic saline, Pediatrics
Aug 2003
– “isotonic saline in 5% dextrose is the safest fluid composition”
• Acute Hyponatremia Related to IV fluid administration in
hospitalized children: An observational study
– 1586 patients admitted to hospital; 40 developed hyponatremia
– 2 with major neurologic sequalae, 1 death
– These patients received sig. more free water than age matched
controls
– Support isotonic fluids for maintenance
Differential Diagnosis
• SIADH must be differentiated from
hypervolemic, hypovolemic and other forms of
euvolemic hypernatremia
• Hypervolemic hyponatremia
– Cirrhosis, CHF
– Always associated with edema
– Osmotic regulation of ADH overwhelmed by a
reduction in effective circulating volume, which stims
ADH release
– Secondary to hypovolemia, renin and aldosterone are
increased, so there is no natriuresis
Differential Diagnosis
• Hypovolemic hyponatremia
– Diuretic abuse, AGE, mineralocorticoid
deficiency
– Excessive loss of Na and H2O
– Associated with signs of hypovolemia:
tachycardia, hypotension
Diagnosis
•Urine osmolality >100mOsm/kg of water
during hypotonicity
•Urine sodium concentration >40 mEq/L
with normal dietary salt intake
•Euvolemic hyponatremia <134, Plasma
Osmolarity <275mOsm/L
Treatment
• Eliminate the source..
• If not:
• If hyponatremia is mild and more than
48hrs duration
– Decrease fluid intake below insensible losses,
which will slowly increase Na.
– Watch for spontaneous remission of SIADH
• Can occur at any time, resulting in brisk diuresis
and a faster increase in serum Na than desired
Treatment
• If hyponatremia is severe (accompanied
with neuro symptoms) or of less than 48
hours duration
– Slow 3% infusion
– Raise Na to point of cessation of symptoms
– After above, no faster than 2 mEq/L per hour
Cerebral Salt Wasting
Harrigan, Mark Cerebral salt wasting syndrome Critical Care Clinics,
Jan 2001
Definition
• A diagnosis of exclusion
• Requires:
– A cerebral lesion
– Renal Na and Cl wasting
• Implies that above were excreted WITHOUT
physiologic stimulus
– Which means you need to have:
– A contracted effective arterial blood volume
• So patient must not have
– A physiologic cause for Na and Cl excretion
• an expanded effective circulating arterial volume
– A condition that may cause a deficiency of Na
resorption
• Aldosterone deficiency
• diuretics
Pathophysiology
• Natriuretic Factors
• Direct Neural effects
Pathophysiology –
Natriuretic Factors
• ANP
– 28 amino acid polypeptide
– Effects:
• Natriuresis
• Diuresis
• Vasodilation
• Suppression of renin and aldosterone secretion
Pathophysiology –
Natriuretic Factors
• ANP
– Released in response to atrial stretch
– CNS modulates ANP secretion
• lesions of specific areas in hypothalamus decrease cardiac
•
secretion of ANP in response to volume expansion
So, intracranial disease may lead to a disturbance in its
control over ANP secretion
– 6/8 neurosurg pts had elevated ANP levels, with a correlation
between ANP level and degree of hyponatremia
– After SAH, ADH and ANP levels elevated on days 0-2, ANP
levels remained high after one week, when ADH levels declined
 SIADH and CSW may co-exist, complicating diagnosis
Pathophysiology –
Natriuretic Factors
• ANP
– However….
– A regression analysis of 15 patients with CSW
secondary to TB mening, found plasma ANP
levels accounted for only 65% of variation in
plasma Na.
– Two other factors may play a role
• BNP
– Of cardiac ventricular origin
• Also localized in hypothalamus
– Secreted in response to increased pressure or stretch
– Similar effects to ANP
– BNP levels are elevated in patients with SAH
– Acute intracranial disease may cause release of
cardiac BNP, and hypothalamic damage may also
release BNP
• Plasma Natriuretic factor
–?
A little more on BNP……
• 40 patients with SAH, BNP levels measured
– Change in, not absolute value of, BNP level independently
associated with hyponatremia
– In those in whom vasospasm developed, BNP levels increased
5.4x within 24 hours, and 11.2x within 3 days
• BNP level independently associated with vasospasm
• Increase in BNP did not precede vasospasm, but increased
concurrently
– May be a good marker….
– Patients with increasing BNP levels after admission had NO
CHANGE in their admit GCS after two weeks
– Patients with no change, or decrease in BNP, had a 3 point
improvement in GCS 2 weeks after admission
McGirt, MJ CORRELATION OF SERUM BRAIN NATRIURETIC PEPTIDE WITH HYPONATREMIA AND DELAYED ISCHEMIC
NEUROLOGICAL DEFICITS AFTER SUBARACHNOID HEMORRHAGE, Neurosurgery June 2004
Direct Neural Effects
• Generalized hyperactivity of the sympathetic
nervous system occurs after SAH
– Sustained activity leads to a decrease in plasma
volume and blood volume
• Acute brain injury may lead to an interruption in
sympathetic flow to kidneys
– Increases glomerular blood flow, GFR and thus
diuresis
– Decreases renin release, and promotes natriuresis
Diagnosis
• Because those patients at risk for CSW,
are also at risk for SIADH, the two must
be distinguished…
CSW
SIADH
*Hypovolemia
clinical dehydration
low CVP
Negative salt balance
Markedly elevated Una
Elevated K with hypoNa
Serum ADH and ANP not
*Euvolemia or
hypervolemia
Variable Una
Normal K
helpful
Likely that SIADH and CSW, in the setting of head
injury/surgery, represent two opposite ends of a spectrum:
•
• pt’s probably have both exaggerated natriuresis and elevated ADH
release, and which effect predominates depends on relative intensities
Treatment
• Treat underlying process
• Volume and sodium replacement
• NS, 3% NaCl, or enteral salt for restoring NaCl
balance
– Enteral salt preferable if euvolemia already restored
• Volume expansion can lead to increased aldosterone, which
can then promote more Na loss
• Restore Euvolemia
• Fludrocortisone
– Works on renal tubule to increase Na reabsorption
– 0.05-0.1 mg/day